Non membrane lysis mechanism of anticancer peptides

The mechanism of action of anticancer peptides is not only to alter the permeability of cancer cell membranes, but also to interact with endogenous targets of cancer cells, thereby inducing cancer cell death (Figure 2).

2.2.1 Induction of apoptosis pathway

Numerous studies have shown that anticancer peptides exert anti-tumor effects by inducing cell apoptosis, manifested as cytoplasmic shrinkage, phosphatidylserine eversion, chromatin condensation, DNA fragmentation, and nuclear membrane nucleolar fragmentation. Apoptosis is divided into endogenous apoptosis (mitochondrial pathway) and exogenous apoptosis (death receptor pathway), with caspase-9 and -8 being the hallmark intermediate activators of both, caspase-3, 6 and 7 are common apoptotic executors of both. In recent years, there have also been research reports that the apoptotic pathway does not require activation of Caspase, but rather promotes nuclear transfer of apoptosis inducing factor (AIF) and endonuclease G (EndoG) in the intermembrane space of mitochondria, leading to DNA fragmentation and chromatin agglutination. So the main pathways of apoptosis include mitochondrial pathway (endogenous), death receptor pathway (exogenous), and non caspase activation pathway.

Mitochondrial pathway representative: Buforin IIb, an anticancer peptide from the Chinese toad, can target 62 types of cancer cells, disrupt mitochondrial membranes, release cytochrome C, and activate caspase cascades, inducing a series of protein hydrolysis reactions leading to cell disintegration (endogenous apoptosis);

Representative of the mitochondrial binding death receptor pathway: RGD tachyplesin I can inhibit tumor growth both in vitro and in vivo, and activate the expression of caspase-3,6,7,8,9 and fas ligand related death domains;

Non Caspase pathway representative: LL-37 effectively activates the expression of the tumor suppressor gene p53 in cells, thereby inducing the expression of multiple transcriptional targets including pro apoptotic proteins of the Bcl-2 family such as BAX, Bak, and Puma. These factors can promote changes in mitochondrial physiological function, thereby releasing AIF and EndoG into the nucleus to perform apoptotic functions. HN-1 (Hainan wild frog antimicrobial peptide) selectively kills breast cancer MCF-7, depending on the Caspase free pathway.